This invention relates to a novel class of compounds which exhibit analgesic activity.
Recently, endogenous substances having morphine-like properties have been extracted fron mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature 258, 577 (1975) as pentapeptides having the following sequences:
H-Tyr-Gly-Gly-Phe-Met-OH PA0 H-Tyr-Gly-Gly-Phe-Leu-OH. PA0 Abu--.alpha.-aminobutyric acid PA0 Ala--alanine PA0 Cys--cysteine PA0 Cys(Me)--(S-methyl)cysteine PA0 Cys(Me)(O)--(S-methyl)cysteine sulfoxide PA0 Gly--glycine PA0 Gly(Al)--allylglycine PA0 Gly(Cp)--cyclopropylmethylglycine PA0 Hse--homoserine PA0 Ile--isoleucine PA0 Leu--leucine PA0 Met--methionine PA0 Met(O)--methionine sulfoxide PA0 Nle--norleucine PA0 Nva--norvaline PA0 Phe--phenylalanine PA0 Phe--N--1 benzyl-2-dimethylaminoethylamine PA0 Ser--serine PA0 Ser(Me)--O-methylserine PA0 Thr--threonine PA0 Tyr--tyrosine PA0 Val--valine PA0 Ac--acetyl PA0 AcOMe--acetoxymethyl PA0 Al--allyl PA0 Cp-cyclopropylmethyl PA0 Me--methyl PA0 Et--ethyl PA0 Ip--isopropyl PA0 Pr--n-propyl PA0 OMe--methoxy PA0 Etm--ethylthiomethyl PA0 Fle--2-fluoroethyl PA0 Ppg--propargyl PA0 Bu--n-butyl PA0 i-Bu--isobutyl PA0 t-Bu--t-butyl PA0 s-Bu--sec-butyl PA0 Boc--t-butyloxycarbonyl PA0 Bzl--benzyl PA0 Cbz--benzyloxycarbonyl PA0 DCC--N,N'-dicyclohexylcarbodiimide PA0 HOBt--1-hydroxybenzotriazole PA0 DMF--N,N-dimethylformamide PA0 TFA--trifluoroacetic acid PA0 THF--tetrahydrofuran PA0 DEAE--diethylaminoethyl PA0 NMM--N-methylmorpholine PA0 IBCF--isobutyl chloroformate PA0 18-crown-6--1,4,7,10,13,16-hexaoxacyclooctadecane PA0 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-N; PA0 H-L-Tyr-D-Abu-Gly-L-(N-Pr)Phe(m-Br)-N; PA0 H-L-Tyr-D-Abu-Gly-L-(N-Et)Phe-N; PA0 H-L-Tyr-D-Nva-Gly-L-(N-Ppg)Phe(p-Me)-N; PA0 H-L-Tyr-D-Nva-Gly-L-(N-Et)Phe(m-OMe)-N; PA0 H-L-Tyr-D-Val-Gly-L-(N-Et)Phe(p-F)-N; PA0 H-L-Tyr-D-Val-Gly-L-(N-Pr)Phe(p-Cl)-N; PA0 H-L-Tyr-D-Nle-Gly-L-Phe(m-I)-N; PA0 H-L-Tyr-D-Nle-Gly-L-(N-Ppg)Phe-N; PA0 H-L-Tyr-D-Leu-Gly-L-(N-Etm)Phe-N; PA0 H-L-Tyr-D-Leu-Gly-L-Phe-N; PA0 H-L-Tyr-D-Ile-Gly-L-(N-Al)Phe(m-Br)-N; PA0 H-L-Tyr-D-Ile-Gly-L-(N-Cp)Phe(p-Et)-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Et)Phe(p-OH)-N; PA0 H-L-Tyr-D-Ala-Gly-L-Phe(p-OEt)-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Fle)Phe(o-Cl)-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Etm)Phe(m-I)-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Fle)Phe(p-I)-N; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N; PA0 H-L-Tyr-D-Ala-Gly-L-Phe-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Al)Phe-N; PA0 H-L-Tyr-D-Ala-Gly-L-(N-Ppg)Phe-N; PA0 H-L-Tyr-D-Thr-Gly-L-(N-Cp)Phe-N; PA0 H-L-Tyr-D-Val-Gly-L-(N-Et)Phe-N; PA0 H-L-Tyr-D-Leu-Gly-L-(N-Et)Phe(m-Br)-N; PA0 H-L-Tyr-D-Val-Gly-L-Phe(m-Br)-N; PA0 H-L-Tyr-D-Leu-Gly-L-(N-Al)Phe(p-F)-N; PA0 H-L-Tyr-D-Thr-Gly-L-Phe(p-CF.sub.3)-N; PA0 H-L-Tyr-D-Thr-Gly-L-(N-Et)Phe(p-OEt)-N; PA0 H-L-Tyr-D-Thr-Gly-L-(N-Me)Phe(m-Br)-N; PA0 H-L-Tyr-D-Thr-Gly-L-(N-Pr)Phe(p-Br)-N; PA0 H-L-Tyr-D-Thr-Gly-L-(N-Al)Phe(m-Cl)-N; PA0 H-L-Tyr-D-Gly(Al)-Gly-L-(N-Et)Phe(p-Et)-N; PA0 H-L-Tyr-D-Gly(Cp)-Gly-L-(N-Me)Phe-N; PA0 H-L-Tyr-D-Met-Gly-L-(N-Et)Phe-N; PA0 H-L-Tyr-D-Cys(Me)-Gly-L-(N-Cp)Phe(o-Br)-N; PA0 H-L-Tyr-D-Met(O)-Gly-L-(N-Pr)Phe-N; PA0 H-L-Tyr-D-Cys(Me)(O)-Gly-L-Phe(m-Br)-N; PA0 H-L-Tyr-D-Ser-Gly-L-Phe(m-I)-N; PA0 H-L-Tyr-D-Ser-Gly-L-(N-Et)Phe(p-Cl)-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Cp)Phe-N; PA0 (N-Me)-L-Tyr-D-Thr-Gly-L-(N-Et)Phe(p-I)-N; PA0 H-L-Tyr-D-Hse-Gly-L-(N-Cp)Phe-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe(m-Br)-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-N; PA0 (N-Et)-L-Tyr-D-Abu-Gly-L-(N-Cp)Phe(p-I)-N; PA0 (N-Me)-L-Tyr-D-Val-Gly-L-Phe(p-Pr)-N; PA0 (N-Pr)-L-Tyr-D-Leu-Gly-L-(N-Cp)Phe(p-CF.sub.3)-N; PA0 H-L-Tyr-D-Abu-Gly-L-(N-Al)Phe(m-OMe)-N; PA0 H-L-Tyr-D-Nle-Gly-L-(N-Al)Phe(o-Br)-N; PA0 H-L-Tyr-D-Ile-Gly-L-(N-Ppg)Phe(p-Br)-N; PA0 (N-Me)-L-Tyr-D-Leu-Gly-L-(N-Et)Phe(m-Br)-N; PA0 (N-Me)-L-Tyr-D-Nva-Gly-L-(N-Me)Phe(p-Ip)-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Ppg)Phe(p-Pr)-N; PA0 (N-Et)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-N; PA0 (N-Cpm)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Cp)Phe-N; PA0 (N-Al)-L-Tyr-D-Ala-Gly-L-(N-Al)Phe-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Etm)Phe-N; PA0 (N-Et)-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-N; PA0 (N-Cpm)-L-Tyr-D-Ala-Gly-L-(N-Et)Phe(m-Me)-N; PA0 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Al)Phe(p-OEt)-N;
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although methionine and leucine enkephalin have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
Therefore, since the discovery of the enkephalins, much effort has been devoted to preparing analogs of the enkephalins in the hope of finding compounds having enhanced activity and practical utility due to their bioavailability by parenteral or oral administration.
Dutta et al., Life Sciences 21, pp. 559-562 (1977) report certain structure modifications which, they suggest, tend to enhance potency. They suggest activity can be enhanced by any or all of the following:
(a) substitution of Gly in position 2 by certain D- or .alpha.-aza-amino acids;
(b) conversion of the terminal carboxyl to the methyl ester or the amide;
(c) modification of the Phe in the 4-position by .alpha.-aza substitution, N-methylation, or hydrogenation of the aromatic ring.
In addition, Roemer et al., Nature 268, pp. 547-549 (1977), suggest modification of the Met.sup.5 to its corresponding carbinol and oxidation of the Met sulfur to the sulfoxide as useful modifications.
Another structural modification of significance is that reported in U.S. Pat. No. 4,322,342. This publication suggests enhancement of activity and bioavailability of enkephalin analogs by insertion of a D-amino acid residue in position 2, conversion of the terminal carboxyl to an amide, and N-alkylation of the amino acid residue in position 5.
Roques et al., Eur. J. Pharmacol. 60, 109-110 (1979), describe, among others, Tyr-D-Ala-Gly-NH(phenethyl), Tyr-D-Ala-Gly-NH-CH(CH.sub.3)CH.sub.2 CH(CH.sub.3).sub.2, and Tyr-D-Met-Gly-NH-CH(CH.sub.3)CH.sub.2 CH(CH.sub.3).sub.2.
Kiso et al., Eur. J. Pharmacol. 71, 347-348 (1981), describe among others, Tyr-D-Met(O)-Gly-NH-(phenethyl) and Tyr-D-Met(O)-Gly-N(CH.sub.3)(phenethyl).
U.S. Pat. No. 4,320,051 describes compounds which include, among others, ##STR2##
A new class of compounds has been discovered which exhibit analgesic activity and which have markedly low levels of physical dependence liability. These compounds are substituted tripeptides, the C-terminal portion of which contains a dimethylamino group.